Although bone cells possess the capacity to repair major insults due to traumatic injury, degeneration or disease often requires surgical intervention and bone grafting. In the United States, approximately 550,000 million fractures annually require bone grafting. Further, of the over 1 million bone grafts performed annually worldwide, 50% involve spinal fusions and 25% of these patients complain of donor site pain from the autograft harvest site for up to two years post-operation. This number does not include the millions of total joint arthroplasties, spinal arthrodeses, maxillofacial surgeries and implant fixations that require bone replacement or repair. In an effort to circumvent the obstacles associated with grafts and complications involved in spinal fusions, researchers have used explored alternative methods such as the use of osteoinductive growth factors instead, including bone morphogenetic proteins (“BMPs”). In particular, BMPs possess the ability to induce heterotopic ossification or de novo bone formation at targeted locations. For example, the FDA recently approved BMP-2 for use in spinal arthrodesis.
Conventional delivery methods of BMP often include administration of isolated recombinant human BMP (rhBMP) in relatively pure in solution to the targeted locations to induce bone growth. The patient's body, however, rapidly clears the BMP when the protein is administered in solution because BMPs are soluable. In particular, BMP cannot be localized and tends to diffuse from the desired site.
As such, the efficacy of BMP is reduced when it is administered by conventional methods, thereby requiring larger doses to attain a therapeutic effect. Because large quantities of the purified BMPs are required to compensate for the rapid diffusion and produce satisfactory bone healing, the grafting procedures can become very expensive. Further, the high dosage of BMP, e.g., supra-physiologic concentrations, may lead to adverse effects such as soft tissue edema, erythema, local inflammation, immune response, and bone resorption in the graft area. Consequently, despite the benefits provided by BMP, many clinicians have found rhBMP to have inconsistent efficacy, especially in complex clinical scenarios such as traumatic injury. These findings have led to a renewed emphasis to develop better methods of delivering BMP to and maintaining BMP at the targeted locations.
Other conventional methods addressed the rapid clearance problem by introducing a delivery system that can retain and sequester the BMPs at the implantation sites. The main role of the delivery system consequently is to retain the growth factor at the defect site for the bone regeneration and repair pertinent duration of time according to defect anatomical site, size and vascularity in order to allow the regenerative tissue forming cells to migrate to the defect area, proliferate and differentiate. For instance, purified BMPs have been integrated with gelatin foam or into collagen sponge or other implantable scaffolding carriers that show some degree of natural binding affinity to BMPs, such as collagen. In particular, the FDA has also approved rhBMP-2 for use on collagen sponges for the treatment of open long bone fractures and in metal cages for spinal fusion.
Unfortunately, these delivery systems have numerous disadvantages. For example, collagen can elicit an adverse immune response from the patient's body. Furthermore, collagen often presents handling difficulties because collagen paste only allows bone surrounding the paste to form but not elsewhere while free-form collagen would diffuse away from the targeted location. Also, the use of a collagen sponge or other implantable delivery devices would bind to the BMPs themselves, thereby reducing the bioavailability of BMPs. Thus, even larger amounts of purified BMP are necessary for a therapeutic response.
Moreover, with respect to spinal fusion, although the use of rhBMP for spinal fusion may negate the need for an additional surgical procedure to harvest autograft bone, current methods still necessitate an operation that introduces a permanent foreign object into the body. In particular, the use of BMP-2 to induce spinal fusion requires that the protein be implanted in a metal cage, leaving the treatment dependent on synthetic implants rather than being completely biological in nature. Further, autologous bone graft is often harvested to use in place of ectopic bone, which requires an additional extensive surgical procedure. Spinal fusion further requires (1) decortication of the transverse processes of the vertebrae targeted for fusion, (2) stripping of the paraspinous musculature from bone, and (3) a fairly long operative time. Beyond the pain associated with decortication and stripping are other complications. In particular, stripping the musculature compromises the stability afforded by these muscles, disrupts the blood supply to both bone and muscle, and promotes scar formation.
Gene therapy approaches hold much promise in achieving locally high levels of BMP for production of robust heterotopic ossification. However, the efficient transduction of cells posed a problem for many of the currently tested systems resulting in low BMP expression such as known methods of delivering adult stem cells (mesenchymal stem cells [MSCs] isolated from bone marrow, fat, and muscle, among others), along with osteoprogenitors and osteogenic factors to the site of interest. Further, this problem is then exacerbated by inclusion of a collagen sponge or other biomaterial that rapidly binds to the BMP, thereby further reducing its effectiveness. Moreover, although adenoviral vectors producing BMP2 (AdBMP2) have been used to elicit spinal fusion in rats, the transduced cells were surgically implanted with collagen sponges or demineralized bone matrix following decortication of lumbar transverse processes. Such inclusion of a biomaterial and invasive decortication procedures cause undesired inflammation, which potentially weakens bone healing. An example of such invasive procedures is described in Wang J C, Kanim L E A, Yoo S, et al. Effect of regional gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in rats, J of Bone and Joint Surgery 2003; 85:905. Given these drawbacks, there is still a need for methods and systems that are biocompatible, biodegradable, osteoinductive and osteoconductive to effectively and economically deliver the desired amount of BMPs to the targeted locations at lower cost.